2003 issue 2

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Volume 12, issue 2

Review article

The role of abnormal intracellular proteolysis in Alzheimer’s dementia pathogenesis

Tadeusz Pietras1, Piotr Wierzbiński1
1. Pracownia Gerontologii Kliniki Pneumonologii i Alergologii Uniwersytetu Medycznego w Łodzi
Postępy Psychiatrii i Neurologii, 2003, 12 (2), 173-182
Keywords: dementia, secretases, presenilins, amyloid beta

Abstract

Aim – the paper presents one or well documented theories of the origin of dementia in Alzheimer's disease, concerning amyloid-beta precursor protein cleavage.

Review – There at least two pathways of this protein proteolytic degradation, i.e. either amyloidogenic, generating amyloid beta, or non-amyloidogenic, generating soluble proteins. Amyloid beta, which is a major component of senile plaques in the brain of patients with Alzheimer's disease, is generated via the amyloidogenic pathway from amyloid-beta precursor protein through its sequential proteolityc cleavage catalyzed by beta- and gamma-secretases. Beta-secretase and gamma-secretase were identified as membrane-tethered aspartyl proteases. The presenilins are required for the proteolytic cleavage catalyzed by gamma-secretase. Mutations in the genes encoding for presenilins and amyloid-beta precursor protein are the cause of early-onset familial Alzheimer's disease. For these reasons secretases are considered an important therapeutic target in Alzheimer's disease.

Conclusion – The proteolytic cascade hypothesis is well documented, but it may relate only to a small part or pathways leading to the pathology of brain injury with subsequent dementia in Alzheimer's disease.

Address for correspondence:
Dr Tadeusz Pietras, Pracownia Gerontologii Kliniki Pneumonologii i Alergologii
Uniwersytetu Medycznego, ul. Kopcińskiego 22, 90-153 Łódź